Cholangiopathies (Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)) are characterized by the proliferation/loss of cholangiocytes, which are the cells that line the biliary epithelium. During cholestasis, biliary hyperplasia/damage is regulated by both autocrine/paracrine mechanisms. For example, during hyperplastic cholangiocyte proliferation bile duct mass increases and proliferating cholangiocytes release numerous factors like histamine presumably to sustain the increased bile duct mass. In ductopenic states, bile duct mass decreases and cholangiocytes are damaged and unable to maintain biliary homeostasis. We have shown that: (i) cholangiocytes express histamine receptors (HRs) and histidine decarboxylase (HDC), the key enzyme regulating histamine synthesis; (ii) cholangiocytes release histamine; and (iii) inhibition of biliry HDC decreases both hyperplastic and neoplastic cholangiocyte growth and vascular endothelial growth factor (VEGF) by autocrine pathways. Besides the autocrine regulation of cholangiocyte proliferation/loss, paracrine regulation of biliary function by neighboring hepatic cells must be considered. It has been demonstrated in patients with PBC and PSC that histamine plasma levels are higher and that there are increased numbers of hepatic mast cells in the proximity of bile ducts. When activated, hepatic mast cells release numerous factors like histamine into the microenvironment, which we propose influence cholangiocyte proliferative/apoptotic responses in cholangiopathies. In our proposal, we present preliminary data supporting the hypothesis that mast cells infiltrate the liver following damage via c-kit/SCF interaction and that mast cells alte the proliferative response of small and large cholangiocytes in models of liver damage or repair by interaction with H1 and H2 HRs and specific microRNAs. Our proposed studies are innovative and will likely provide important, clinically relevant data to add to the understanding f the regulation of biliary disorders and also offer insight into novel treatment strategies.